Abstract. The impact of a polymorphism of the wild-type human tumour suppressor gene p53(wt) on carcinogenesis is subject of controversy ever since a higher susceptibility of p53 to HPV-E6 mediated degradation when encoding for Arginine at codon 72 (p53 Arg ) was first reported. The issue remained unclear because various studies investigating this question for different tumour entities and different geographical regions demonstrated diverging results. In the present study, the HPV status and p53 genotype frequency of 42 head and neck cancers was analysed and compared to results reported in the recent literature. Applying PCR and cycle sequencing techniques, HPV DNA was demonstrated in 12/42 (29%) of the cases and the overall distribution of the p53 allele was: 64, 31 and 5% for p53 Arg , p53 Arg/Pro and p53 Pro , respectively. There was no statistically significant association between HPV status and p53 genotype distribution. The results of our study and of the reviewed literature do not support a relevant role of the p53 polymorphism in head and neck carcinogenesis, either taken alone or in association with the HPV status.
IntroductionEpidemiology oriented studies strongly confirm the conclusion of the molecular biology based observations, pointing to an etiological involvement of human papillomaviruses (HPV) in a subset of head and neck carcinomas (1,2). Infections with high risk HPV types, most frequently HPV type 16 (HPV16), were shown to be regularly detectable in ~20-30% for oro-, hypopharyngeal as well as laryngeal squamous cell carcinomas and ~60% for squamous cell carcinomas of the Waldeyer's tonsillar ring (1-5). From a mode of action perspective, expression of the viral oncogenes E6 and E7 dysregulates the control of crucial cell mechanisms, particularly the apoptotic pathway and the cell cycle. The E6 gene product binds wildtype p53, triggering its ubiquitin-mediated degradation, thus preventing a cell cycle block and induction of apoptosis of DNA-damaged cells, whereas the E7 protein binds pRb. The corresponding disruption of cell cycle regulation, with downregulation of pRb and cyclin D1 expression as well as upregulation of p16INK4a has been observed in patient derived material (4,6-9). In HNSCC, tumours with lower retinoblastoma gene product (pRb) levels, overexpression of p16
INK4aas well as lack of p53 mutations, viral activity in form of E6/E7 mRNA expression finally leading to carcinogenesis can, most likely, be expected.In wild-type p53 gene, a common AccII restriction fragment length polymorphism in codon 72 of exon 4 (Arg72Pro) has been demonstrated. It arises from a single base pair substitution, and results in either a proline (CCC, p53 Pro ) or an arginine (CGC, p53 Arg ) residue (10).In 1998, Storey et al reported that the p53 Arg protein is more susceptible to E6-mediated proteolytic degradation than the p53 Pro protein and that the p53 Arg allele is over-represented in cervical cancer patients (11). The conclusion that the p53 Arg allele confers a higher risk for cervical cancer deve...